Substituted 2-(heteroaryl-2-propenyl)phenols useful as anti-inflammatory agents

ABSTRACT

Substituted cinnamyl-2,3-dihydrobenzofurans and analogs were prepared from the nucleophlic substitution of a cinnamylhalide with a 2,3-dihydrobenzofuran anion or an analog thereof. These compounds were found to be potent topical anti-inflammatory agents.

This is a division of application Ser. No. 764,446, filed 8/12/85, nowU.S. Pat. No. 4,686,235.

BACKGROUND OF THE INVENTION

The present invention relates to novel substitutedcinnamyl-2,3-dihydrobenzofuran and analogs useful as anti-inflammatoryagents useful as topical anti-inflammatory agents. A number ofcinnamylphenols have been known to have antibiotic activities. Forexample, those disclosed in U.S. Pat. Nos. 3,745,222; 3,775,540;3,777,037; 3,865,748; 3,936,393; 3,951,820; and 4,105,698. However,these patents did not disclose the novel compounds of the presentinvention especially those compounds related to substitutedcinnamyl-2,3-dihydrobenzofurans or its analogs, nor did they disclosethe newly discovered topical anti-inflammatory activity of thesecompounds.

We have found that the novel compounds are active in vitro in both theperitoneal macrophage assay and the polymorphonuclear leukocyte assay.We have also found these compounds are active in vivo in the topicalmouse ear assay and the U.V. erythema assay for anti-inflammatoryagents. However, these compounds tend to be inactivated in vivo andthereby are devoid of any significant systemic effects.

Recent studies demonstrated that macrophages participate in thedevelopment and progression of chronic inflammatory diseases such asrheumatoid arthritis. During the progression of inflammatory conditions,there is generally an appearance and/or presence of macrophages andlymphocytes, especially macrophages and polymorphonuclear leukocytes.Macrophages are known to secrete various products in response toinflammatory stimuli. For example:

(1) Neutral proteinases--the destructive peptide bond cleaving enzymewhich has been shown to be directly involved in rheumatoid cartilagedestruction; and

(2) Prostaglandins (PG) (e.g., E₂ and I₂ by mouse peritonealmacrophages) and other arachidonic acid derivatives derived from boththe cyclooxygenase and the lipoxygenase pathways.

These archidonic acid oxygenation products have been identified as thecritical mediators of various inflammatory conditions.

Interruption of these pathways by enzyme inhibition has been exploredfor effective therapy. For example, non-steroidal anti-inflammatorydrugs (NSAID) such as aspirin, indomethacin and diflunisal are knowncyclooxygenase inhibitors which inhibit the process wherein arachidonicacid is oxygenated via cyclooxygenase to prostaglandins andthromboxanes.

Recently, it has been observed that certain leukotrienes are responsiblefor diseases related to immediate hypersensitivity reactions such ashuman asthma, allergic disorders, and skin diseases. In addition,certain leukotrienes and derivatives thereof are believed to play animportant role in causing inflammation (B. Samuelsson, Science, 220, 568(1983); D. Bailey et al, Ann. Rpts. Med. Chem., 17, 203 (1982)).

Conditions involving elevated intraocular pressures which are too highfor normal function may result in irreversible loss of visual function.For example, glaucoma, if untreated, may lead to ocular hypertension,inflammation, and eventually blindness.

To be an effective and acceptable topical agent, for treatinginflammation in the eye, such as that caused by glaucoma or other eyediseases, the drug must not only penetrate the ophthalmic tissues toreach the active sites within the eye, but it must also be devoid ofthose side effects including irritation, allergic reaction and the likewhich would militate against long term administration.

Accordingly, pharmacological agents which are capable of inhibiting theformation of, the release of a mediator from, or the function ofmacrophages or polymorphonuclear leukocytes may also be effective agentsin the treatment of various inflammatory conditions, e.g., pain, fever,rheumatoid arthritis, osteoarthritis, bronchial inflammation,inflammatory bowel disease, asthema, allergic disorders, skin diseases,cardiovascular disorders, glaucoma, emphysema, acute respiratorydistress syndrome, spondylitis, lupus, gout, psoriasis, and otherprostaglandins and/or leukotriene mediated diseases.

Regarding the topical mouse ear assay, it has been previouslyestablished that classical nonsteroidal anti-inflammatory agents such asindomethacin and steroidal anti-inflammatory agents such as dexamethsoneare active in this assay.

With respect to the U.V. erythema assay, it has been shown previouslythat the U.V. erythema condition is partially the result of a localrelease of prostaglandins derived oxidatively from arachiodonic acid bythe action of PG synthetases, e.g., cyclooxygenase. Therefore,pharmacological agents which inhibit the erythema are generallyconsidered to be active topical anti-inflammatory agents.

Furthermore, anti-inflammatory agents which are not significantlysystemically active are advantageous in the sense that they are notsubject to the adverse effects, e.g., gastrointestinal ulcerations andbleeding that often plagued users of systemic NSAIDs (non-steroidalanti-inflammatory agents). Accordingly, an object of this invention isto provide novel substituted cinnamyl-2,3-dihydrobenzofuran derivativesand analogs as dual enzyme inhibitors of cyclooxygenase and lipoxygenaseand particularly as topical anti-inflammatory agents. These agents areespecially useful in the treatment of, among others, dermal inflammatoryconditions and prusitus such as sunburn, erythema, eczema, contactdermatitis, allergic dermatitis, eye inflammation caused by glaucoma,and psoriasis. They are also useful for topical application to preventperiodontal diseases.

Another object of this invention is to provide appropriate processes forthe preparation of the subject novel compounds.

Still a further object of the present invention is to provide apharmaceutically acceptable composition containing an effective amountof the active compound for the treatment of various dermatologicalinflammatory conditions.

Finally, it is the ultimate object of this invention to develop a methodof treating dermal inflammation via the administration of atherapeutically effective amount of the novel compounds orpharmaceutically acceptable compositions thereof to a mammalian speciesin need of such treatment.

DETAILED DESCRIPTION OF THE INVENTION A. Scope of the Invention

This invention relates to novel compounds of formula (I) and thecorresponding open-chain analogs of formula (II): ##STR1## or apharmaceutically acceptable salt thereof. Wherein

R is

(a) hydroxyloweralkyl;

(b) lower alkanoyl;

(c) CN;

(d) halo;

(e) mercaptoloweralkyl especially mercapto C₁₋₆ alkyl such as --CH₂ SR²where R² represents H or loweralkyl,

(f) loweralkylthio especially C₁₋₆ alkylthio such as --SCH₃ ;

(g) lowerhaloalkyl;

(h) --COOR² ;

(i) hydroxycarbonylloweralkyl especially hydroxycarbonyl-C₁₋₆ alkyl suchas --CH₂ COOH;

(j) loweralkoxycarbonylloweralkyl especially C₁₋₆ alkoxycarbonyl C₁₋₆alkyl such as --CH₂ COO t-Bu;

(k) haloloweralkanoyl especially halo C₁₋₆ alkanoyl such astrifluoroacetyl;

m is 1 to 4;

n is 2 or 3;

A is

(a) phenyl substituted with (R¹)_(q) wherein when there are more thanone R¹ (q 1) R¹ can be the same or different from each other and is

(1) hydrogen;

(2) halo especially fluoro, chloro or bromo;

(3) loweralkoxy especially C₁₋₆ alkoxy, e.g., methoxy, ethoxy,isopropoxy, t-butoxy or cyclohexyloxy, or --OCH₂ O--;

(4) lower alkylthio especially C₁₋₆ alkylthio, or C₁₋₆ haloalkylthioe.g., methylthio, ethylthio, trifluoromethylthio or cyclohexylthio;

(5) lower alkyl sulfinyl especially C₁₋₆ alkyl sulfinyl, e.g., methylsulfinyl, i-propyl sulfinyl, and cyclopentyl sulfinyl;

(6) lower alkyl sulfonyl especially C₁₋₆ alkyl sulfonyl such as methylsulfonyl, ethyl sulfonyl and n-butyl sulfonyl;

(7) unsubstituted or substituted phenyl loweralkoxy such as benzyloxy;

(8) loweralkyl especially C₁₋₆ alkyl such as methyl, ethyl, propyl,t-butyl, pentyl, benzyl, cyclopropyl, cyclopentyl or cyclohexyl;

(9) loweralkenyl especially C₂₋₆ alkenyl, for example, vinyl, allyl, andbuten-2-yl;

(10) lower alkanoyl especially C₁₋₆ alkanoyl such as formyl, acetyl ori-propanoyl;

(11) haloloweralkyl especially C₁₋₆ haloalkyl such as trifluoromethyl;

(12) --COOH;

(13) aryl especially phenyl or substituted phenyl, e.g.,4-methoxyphenyl, 2,4-difluorophenyl or 3-chlorophenyl; or

(14) aryloxy especially phenoxy;

(15) cyano;

(16) hydroxyloweralkyl especially hydroxy C₁₋₃ alkyl such as --CH₂ OH;

(17) halo loweralkanoyl especially haloC₁₋₆ alkanoyl eq. CF₃ CO;

(18) heteroaryl as defined below; or

(19) loweralkanoyloxy especially acetyloxy;

q is 0 to 5;

(b) unsubstituted or substituted heteroaryl, for example:

(1) thienyl;

(2) benzothienyl;

(3) furyl;

(4) benzofuryl;

(5) pyrryl;

(6) indolyl;

(7) thiazolyl;

(8) benzothiazolyl;

(9) thiadiazolyl;

(10) benzothiadiazolyl;

(11) quinolyl;

(12) isoquinolyl;

(13) pyridyl;

(14) pyrazinyl;

(15) tetrazolyl;

(16) triazolyl; or

(17) imidazole;

the heteroaryl above can be substituted with one or more of R¹, e.g.,C₁₋₆ alkyl, C₁₋₆ alkanoyl, C₁₋₆ haloalkyl, halo, cyano, cyano, orhydroxy C₁₋₃ alkyl.

In a preferred embodiment of this invention, the compounds are offormula (II)

wherein

R is

(a) COOR² ;

(b) loweralkoxy;

(c) haloloweralkylcarbonyl especially haloC₁₋₆ alkylcarbonyl such as CF₃CO--;

(d) halo;

(e) loweralkanoyl especially acetyl;

(f) lowerhaloalkyl especially trifluoromethyl;

(g) hydroxyloweralkyl eg. --CH₂ OH; or

(h) cyano;

A is phenyl substituted with (R¹)_(q) where R¹ and q are as previouslydescribed; and

m is 1 to 3.

In a more preferred embodiment of this invention, the compounds are offormula (I)

wherein

A is phenyl substituted with (R¹)_(q) wherein R¹ is

(a) hydrogen;

(b) loweralkoxy;

(c) halo;

(d) lowerhaloalkyl,

(e) loweralkanoyl;

(f) hydroxyloweralkyl; or

(q) CN;

q is 1 or 2; and

n is 2 or 3.

In the even more preferred embodiment of the present invention, thecompounds are of the following formulae: ##STR2## wherein R¹ isloweralkanoyl or hydroxyloweralkyl.

B. Preparation of the Compounds within the Scope of the Invention

The novel compounds of the present invention are prepared from thefollowing processes: ##STR3## Scheme (c) is applicable to thepreparation of a compound of formula I from the aldehyde of formula##STR4##

The procedures of the above synthetic schemes (a) and (b) are known forthe preparation of cinnamylphenols of formula (II), i.e., thosedisclosed in U.S. Pat. Nos. 3,745,222; 3,775,540; 3,777,039; 3,865,748;3,936,393; 3,951,820; and 4,105,698. However, these procedures have notbeen applied to prepare the cinnamyl-2,3-dihydrobenzofuran derivativesof formula (I).

The alkylations described in Schemes (a) and (b) are useful only whenthe cinnamyl bromide (V) is unsubstituted or substituted withelectron-withdrawing groups. Analogs with electron-donating substituentsor with electron-rich heterocycles must be prepared by Scheme (c). Anyanalogs that are prepared by Schemes (a) and (b) may be synthesizedaccording to Scheme (c) by using the appropriate Wittig reagent (IX).This includes cinnamyl-2,3-dihydrobenzofurans which would utilize theWittig reagent XI ##STR5##

C. Utility of the Subject Compounds of the Invention

This invention also relates to a method of treating topical inflammationin patients in need of such treatment. Generally, a sufficient amount ofa compound of formulae (I) or (II) or a pharmaceutical compositionthereof, particularly an especially preferred compound, is administeredto the patient as the active constituent.

The topical mouse ear assay (TME) was used to evaluate the novelcompounds of the present invention for its effect on inflammatoryresponses elicited by topically applied phorbol myristate acetate (PMA)or topically applied archidonic acid (AA). The inflammatory responsesmay be in the form of edema (measured by net weight); vascularpermeability (measured by ¹²⁵ I-BSA accumulation); of PMN infiltration(measured by myeloperoxidase activity). A protocol of the assay and someresults derived therefrom are summarized in Table I.

TABLE I Topical Mouse Ear Assay

Method: The right ears of mice (5 mice per group) were treated topicallywith either 5 μl PMA or 1000 μg AA alone or with the test compound in 25μl of vehicle. The vehicle was water/pyridine/acetone (1:2:97). Acontrol group of mice received the vehicle only. The mice were allowedfood and water ad libitum during the treatment period; 2 hours for AAand 4 hours for PMA. The mice were sacrificed by cervical dislocationand a 6 mm diameter disc of tissue punched from both the treated anduntreated ears. The tissue biopsies were immediately weighed and theweight increase of the treated ear relative to the weight of theuntreated ear determined.

For the determination of vascular permeability, 1 μM ¹²⁵ I-bovine serumalbumin (¹²⁵ I-BSA) was administered in 0.5 ml phosphate buffered saline15 min prior to the topical application. At the termination of theexperiment, the amount of radioactivity in both the treated anduntreated ear biopsies was determined and the increased amount ofradioactivity in the treated tissue relative to the amount ofradioactive in the untreated tissue determined.

As a measure of PMN infiltration, the amount of myeloperoxidase (MPO)activity in the same tissues was determined. The tissue biopsies werehomogenized into 1 ml 0.5% hexadecyltrimethylammonium bromide andcentrifuged for 45 min. at 1200×g. Aliquots 40 μl, of the supernatantphases were assayed for MPO activity by a colorimetric method devised byH. Dougherty for automated Titertek analysis. The MPO activity isexpressed as the OD₄₅₀ of the treated ear homogenate minus the OD₄₅₀ ofthe non-treated ear homogenate.

All of the data are expressed as the mean±SEM, N=5 mice/group.

Results: The effect of5-hydroxy-6-(2-hydroxymethylcinnamyl)-2,3-dihydrobenzofuran (A)

    ______________________________________                                        Compound     Dosage (μg)                                                                           Edema (% inhibition)                                  ______________________________________                                        A            300        88                                                                 150        54                                                                  50        37                                                    Indomethacin 150        51                                                    Dexamethasone                                                                               5         60                                                    ______________________________________                                    

For the treatment of inflammation, arthritis conditions, cardiovasculardisorder, allergy, psoriasis, asthma, or other diseases mediated byprostaglandins and/or leukotrienes, a compound of Formula (I) may beadministered orally, topically, parenterally, by inhalation spray orrectally in dosage unit formulations containing conventional non-toxicpharmaceutically acceptable carriers, adjuvants and vehicles. The termparenteral as used herein includes subcutaneous injections, intravenous,intramuscular, intravascular injection or infusion techniques.

Particularly, the pharmaceutical compositions containing the activeingredient may be in a form suitable for topical use, for example,aqueous or oily solutions or suspensions, dispersible powders orgranules, tinctures, topical aerosol emulsions, creams, ointments,jellies, suppositories or the like. Compositions intended for topicaluse may be prepared according to any method known to the art for themanufacture of pharmaceutical compositions and such compositions maycontain one or more active compounds.

Aqueous suspensions contain the active materials together withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspended agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyoxyethylene sorbitan monooleate.The said aqueous suspensions may also contain one or more preservatives,for example, ethyl, or n-propyl p-hydroxybenzoate.

Oily suspension may be formulated by suspending the active ingredient ina vegetable oil, for example, arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example, beeswax, hardparaffin or cetyl alcohol. These compositions may be preserved by theaddition of an antioxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample, olive oil or arachis oils, or a mineral oil, for example,liquid paraffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example, gum acacia or gum tragacanth,naturally-occurring phosphatides, for example, soy bean lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example, sorbitan mono-oleate, and condensation productsof the said partial esters with ethylene oxide, for example,polyoxyethylene sorbitan monooleate.

An ointment containing the pharmaceutical compositions of the presentinvention may be prepared, among other methods known in the art, bycombining the active ingredient with a medium consisting of a glycol, alower alkanol, and water; a gelling agent; and optionally an adjuvantsuch as diisopropyl adipate, diethyl sebacate, ethyl caproate and ethyllaurate. Suitable glycols include propylene glycol, butylene glycol,polyethylene glycol and the like. Generally, a caboxyvinyl polymerpreneutralized with an organic amine such as diisopropyl amine andtriethylamine, or a cellulose, e.g., hydroxyethyl cellulose, methylcellulose, carboxymethyl cellulose, hydroxypropyl cellulose, is used asthe gelling agent.

The compounds of the invention may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials are cocoa butter and polyethylene glycols.

Dosage levels of the order to 0.2 mg to 140 mg per kilogram of bodyweight per day are useful in the treatment of the above-indicatedconditions (10 mg to 7 gms per patient per day). For example,inflammation may be effectively treated by the administration from about0.5 to 50 mg of the compound per kilogram of body weight per day (25 mgto 5 gms per patient per day). Advantageously, from about 2 mg to about20 mg per kilogram of body weight per daily dosage produces highlyeffective results (50 mg to 1 gm per patient per day).

Particularly, for use in treatment of ophthalmic conditions includingeye inflammation caused by glaucoma or other eye diseases, the activecompound can be administered topically or systemically when it isappropriate. The dose administered can be from as little as 0.1 to 25 mgor more per day, singly, or preferably on a 2 to 4 dose per day regimenalthough a single dose per day is satisfactory.

When given systemically, the drug can be given by any route, althoughthe oral route is preferred. In oral administration the drug can beemployed in any of the usual dosage forms such as tablets or capsules,either in a contemporaneous delivery or sustained release form. Anynumber of the usual excipients or tableting aids can likewise beincluded.

When given by the topical route, the active drug or anophthalmologically acceptable salt thereof such as the sodium orpotassium salt is formulated into an ophthalmic preparation. In suchformulations, from 0.1% to 15% by weight can be employed. The objectiveis to administer a dose of from 0.1 to 10 mg per eye per day to thepatient, with treatment continuing so long as the condition persists.

The active drugs of this invention are most suitably administered in theform of ophthalmic pharmaceutical compositions adapted for topicaladministration to the eye such as a suspension, ointment, or as a solidinsert. Formulations of these compounds may contain from 0.01 to 15% andespecially 0.5% to 2% of medicament. Higher dosages as, for example,about 10%, or lower dosages can be employed provided the dose iseffective in reducing or controlling inflammation. As a unit dosage frombetween 0.001 to 10.0 mg, preferably 0.005 to 2.0 mg, and especially 0.1to 1.0 mg of the compound is generally applied to the human eye,generally on a daily basis in single or divided doses so long as thecondition being treated exists.

The pharmaceutical preparation which contains the active compound may beconveniently admixed with a non-toxic pharmaceutical organic carrier, orwith a non-toxic pharmaceutical inorganic carrier. Typical ofpharmaceutically acceptable carriers are, for example, water, mixturesof water and water-miscible solvents such as lower alkanols oraralkanols, vegetable oils, polyalkylene glycols, petroleum based jelly,ethyl cellulose, ethyl oleate, carboxymethylcellulose,polyvinylpyrrolidone, isopropyl myristate and other conventionallyemployed acceptable carriers. The pharmaceutical preparation may alsocontain non-toxic auxiliary substances such as emulsifying, preserving,wetting agents, bodying agents and the like, as for example,polyethylene glycols 200, 300, 400 and 600, carbowaxes 1,000, 1,500,4,000, 6,000 and 10,000, antibacterial components such as quaternaryammonium compounds, phenylmercuric salts known to have cold sterilizingproperties and which are non-injurious in use, thimerosal, methyl andpropyl paraben, benzyl alcohol, phenyl ethanol, buffering ingredientssuch as sodium chloride, sodium borate, sodium acetates, gluconatebuffers, and other conventional ingredients such as sorbitanmonolaurate, triethanolamine, oleate, polyoxyethylene sorbitanmonopalmitylate, dioctyl sodium sulfosuccinate, monothioglycerol,thiosorbitol, ethylenediamine tetraacetic acid, and the like.Additionally, suitable ophthalmic vehicles can be used as carrier mediafor the present purpose including conventional phosphate buffer vehiclesystems, isotonic boric acid vehicles, isotonic sodium chloridevehicles, isotonic sodium borate vehicles and the like.

The pharmaceutical preparation may also be in the form of a solid insertsuch as one which after dispensing the drug remains essentially intact,or a bio-erodible insert that either is soluble in lacrimal fluids, orotherwise disintegrates.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. Dosage unitforms will generally contain between from about 25 mg to about 1 g ofactive ingredient.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, rate of excretion, drug combination and the severity ofthe particular disease undergoing therapy.

Set forth below are some illustrative topical formulations containing aselected active compound of the instant invention.

FORMULATION 1-SOLUTION

(a) Distilled water qs to 100%

Procedure: Dissolve compound (A) in enough water to make 100%. Filterthe solution. Apply to the affected area.

FORMULATION 2-TINCTURE

(b) Alcohol U.S.P.--50%

Water qs to 100%

Procedure: Dissolve compound (A) in the alcohol. Add sufficient water tomake 100%. Filter and apply to affected area.

FORMULATION 3-TOPICAL AEROSOL

(c) Alcohol U.S.P.--5%

Isopropylmyristate--5%

Conventional halogenated hydrocarbon propellant qs 100% e.g., Freon 11(trichlorofuluromethane), Freon 12 (dichlorodifluoromethane), Freon 14(carbon tetrafluoride), Freon C 318 (Octafluorocyclobutane), Freon 114(Cryofluorane), etc.

Procedure: Dissolve Compound (A) in the alcohol and isopropylmyristate.Add sufficient halogenated propellant and introduce into conventionalaerosol containers either by pressure or by cold filing. Apply toaffected area.

FORMULATION 4-OINTMENT

Petrolatum U.S.P. qs to--100%

Procedure: Heat the petrolatum to 60° C. Add compound (A) and stir untilthoroughly dispersed. Cool to room temperature. Apply to affected area.

FORMULATION 5

    ______________________________________                                        A Compound of formula (I)                                                                          1     mg.    15   mg.                                    Monobasic sodium phosphate.2H.sub.2 O                                                              10    mg.    5    mg.                                    Dibasic sodium phosphate.12H.sub.2 O                                                               30    mg.    15   mg.                                    Benzalkonium chloride                                                                              0.1   mg.    0.1  mg.                                    Water for injection q.s. ad.                                                                       1.0   ml.    1.0  ml.                                    ______________________________________                                    

A compound of formula (I), phosphate buffer salts, and benzalkoniumchloride are added to and dissolved in water. The pH of the compositionis adjusted to 6.8 and diluted to volume. The composition is renderedsterile by ionizing radiation.

FORMULATION 6

    ______________________________________                                        A Compound of formula (I)                                                                         5         mg.                                             petrolatum q.s. ad. 1         gram                                            ______________________________________                                    

The active compound and the petrolatum are aseptically combined.

FORMULATION 7

    ______________________________________                                        A Compound of formula (I)                                                                           1 mg.                                                   Hydroxypropylcellulose q.s.                                                                        12 mg.                                                   ______________________________________                                    

Ophthalmic inserts are manufactured from compression molded films whichare prepared on a Carver Press by subjecting the powdered mixture of theabove ingredients to a compressional force of 12,000 lbs. (gauge) at300° F. for one to four minutes. The film is cooled under pressure byhaving cold water circulate in the platen. Ophthalmic inserts are thenindividually cut from the film with a rod-shaped punch. Each insert isplaced into a vial, which is then placed in a humidity cabinet (88% R.H.at 30° C.) for two to four days. After removal from the humiditycabinet, the vials are stoppered and then capped. The vials containingthe hydrate insert are then autoclaved at 250° F. for 1/2 hour.

FORMULATION 8

    ______________________________________                                        A Compound of formula (I)                                                                           1 mg.                                                   Hydroxypropyl cellulose q.s. ad.                                                                   12 mg.                                                   ______________________________________                                    

Ophthalmic inserts are manufactured from a solvent cast film prepared bymaking a viscous solution of the powdered ingredients listed above usingmethanol as the solvent. The solution is placed on a Teflon plate andallowed to dry at ambient conditions. After drying, the film is placedin an 88% R.H. cabinet until it is pliable. Appropriately sized insertsare cut from the film.

FORMULATION 9

    ______________________________________                                        A Compound of formula (I)                                                                             1 mg.                                                 Hydroxypropylmethyl cellulose q.s. ad.                                                               12 mg.                                                 ______________________________________                                    

Ophthalmic inserts are manufactured from a solvent cast film which isprepared by making a viscous solution of the powdered blend of the aboveingredients using a methanol/water solvent system (10 ml. methanol isadded to 2.5 g. of the powdered blend, to which 11 ml. of water (inthree divided portions) is added. The solution is placed on a Teflonplate and allowed to dry at ambient conditions. After drying, the filmis placed in an 88% R.H. cabinet until it is pliable. Appropriatelysized inserts are then cut from the film.

FORMULATION 10

    ______________________________________                                        A Compound of formula (I)                                                                             1 mg.                                                 Hydroxypropylmethyl cellulose q.s. ad.                                                               12 mg.                                                 ______________________________________                                    

Ophthalmic inserts are manufactured from compression molded films whichare prepared on a Carver Press by subjecting the powdered mixture of theabove ingredients to a compressional force of 12,000 lbs. (gauge) at350° F. for one minute. The film is cooled under pressure by having coldwater circulate in the platen. Ophthalmic inserts are then individuallycut from the film with a punch. Each insert is placed into a vial, whichis then placed in a humidity cabinet (88% R.H. at 30° C.) for two tofour days. After removal from the humidity cabinet, the vials arestoppered and then capped. The vials containing the hydrated insert arethen autoclaved at 250° F. for one-half hour.

It is highly preferred that the solid inserts of this invention areavailable for use by the patient in a pathogen free condition. Thus, itis preferred to sterilize the inserts and to insure againstrecontamination, the sterilization is preferably conducted afterpackaging. The best mode of sterilizing is to employ ionizing radiationincluding radiation emanating from Cobalt 60 or high energy electronbeams.

FORMULATION 11

The following materials are admixed in a 1250 ml bottle: 24 g of anactive compound, e.g.,5-hydroxy-6-(2-hydroxymethylcinnamyl)-2,3-dihydrobenzofuran, which is asufficient amount of medicament to result in a concentration of 10 mgper ml in the final samples, allowing for previously established 3.0%average; 0.4 g sodium bisulfite, 12 g NaCl, and 28 ml water (at 180°F.). This mixture, (I), is autoclaved for 30 minutes at 121° C. under 15psig. Separately, 3 g of hydroxyethylcellulose in 720 ml of water (II)and 0.4 g of lecithin in 80 ml of water (III) were autoclaved for 30minutes at 121° C. Then, (III) is admixed with (I) for 2 hours, and theresultant mixture poured into (II). Another mixture (IV) is preparedfrom 20 g of sorbitol, 2.36 ml of benzalkonium chloride, 10 g ofdisodium edetate, and water to give a final solution volume of 900 ml.Then, (IV) is added to the mixture of (I), (II), and (III) in sufficientquantity to give 1.8 l. overall. The 1.8 l. mixture of I, II, III, andIV is then taken and homogenized using a homogenizer at 2000 psig. Stocksolutions are then prepared for polyoxyethylene (20) sorbitan monooleateby dissolving 3 g of the material in 100 ml of water, and of benzylalcohol/β-phenyl-ethyl alcohol by admixing 50 ml of each alcohol.Varying quantities of the two stock solutions are then added to four 90ml aliquots of the homogenized mixture of (I), (II), (III), and (IV)prepared as described above, together with sufficient water to give atotal of 100 ml for each of four different samples.

FORMULATION 12 Solution Composition

    ______________________________________                                        5-hydroxy-6-(2-hydroxymethyl-                                                                      0.1       mg.                                            cinnamyl)-2,3-dihydrobenzofuran                                               Peanut oil q.s. ad.  0.11      mg.                                            ______________________________________                                    

The solution is rendered sterile by filtration through a sterilizingfilter.

FORMULATION 13

    ______________________________________                                        A compound of formula (I)                                                                         0.5       gm.                                             Petrolatum q.s. ad. 1         gram                                            ______________________________________                                    

The compound and the petroleum are aspetically combined.

EXAMPLE 1 6-cinnamyl-2,3-dihydro-5-hydroxybenzofuran

Sodium hydride (0.40 g; 10 mM; 60% in mineral oil) was washed twice withhexane under nitrogen. The sodium hydride was suspended in 15 ml ofbenzene and 5-hydroxy-2,3-dihydrobenzofuran (1.00 g; 7.37 mM) was addedin 20 ml of benzene in one portion. The suspension was stirred at roomtemperature for 1.5 hours giving a pale blue suspension. Cinnamylbromide (freshly distilled; b.p.=76°-8° at 0.2 torr; 1.58 g; 8.0 mM) wasadded in 15 ml of benzene. The reaction was then heated to reflux for3.5 hours. After cooling the reaction mixture was poured into 1N aqueoushydrochloric acid, partitioned and back extracted with ether. Thecombined organic layers were dried over magnesium sulfate, filtered, andstripped to a brown oil. The crude reaction product was flashchromatographed with 600 ml of 20% ethyl acetate in hexane on a 30 mm by6" column of silica gel. This chromatography gave a mixture of productand starting phenol which were separated by chromatography on onecartridge in the Waters Prep 500 with 2 gallons of 20% ethyl acetate inhexane and four recycles with peak having techniques. The resultingsemipurified product was crystallized from benzene/hexane to 0.516 g(28% yield). of 6-cinnamyl-2,3-dihydro-5-hydroxybenzofuran.

NMR (CDCl₃): δ 7.0-7.3 (m; 4H); 6.16-6.62 (m; 4H); 4.43 (s; 1H); 4.40 (t(8 Hz); 2H); 3.40 (d(5 Hz); 2H); 3.03 (t(8 Hz); 2H).

IR: 3700, 2920, 1610, 1490, 1425, 1140, 981, 870 cm⁻¹ (CHCl₃).

MS: 252 (M+) (68%); 161 (34%); 148 (100%); 91 (36%).

    ______________________________________                                        Microanalysis:     C      H                                                   ______________________________________                                        Calculated:        80.92  6.39                                                Found:             80.50  6.05                                                ______________________________________                                    

m.p.=85°-87° C.

EXAMPLE 2 6-(o-Bromocinnamyl)-2,3-dihydro-5-hydrobenzofuran Step A:Preparation of o-bromocinnamylalcohol

Ethyl o-bromocinnamate (66.3 g; 260 mM) was dissolved in 750 ml ofanhydrous toluene under nitrogen in a three-neck round bottom flaskequipped with addition funnel and condensor. A toluene solution ofdiisobutylaluminum hydride (520 mM; 1.53M) was transferred via canula tothe addition funnel and then added dropwise to the reaction mixture,which had been chilled to -78°. After the addition was completed thereaction was warmed to ambient temperature over a 1.5 hour period andquenched by the dropwise addition of 50 ml of water. Some cooling wasrequired. The resulting emulsion was added to 640 ml of 2N aqueoushydrochloric acid. After partitioning the slightly acidic (pH 5) aqueouslayer was extracted twice with ether. The combined organic fractionswere dried (MgSO₄), filtered (fritted funnel), and evaporated to affordan oil. The oil was chromatographed in two portions on the Waters Prep500 equipped with two cartridges eluting with a total of two gallons of35% ethyl acetate in hexane. This produced 33.8 g (61% yield) ofo-bromocinnamylalcohol. NMR (CDCl₃): δ 6.8-7.8 (m; 5H); 6.0-6.6 (AB;1H); 4.2-4.4 (brd.; 2H); 2-2.6 (brs; 1H).

Step B: Preparation of o-bromocinnamylbromide

All of the o-bromocinnamylalcohol (159 mM) from Step A was dissolved in300 ml of carbon tetrachloride under nitrogen and chilled to 0°. Then100 ml of carbon tetrachloride containing phosphorous tribromide (5.62ml; 59.8 mM) was added dropwise. After stirring at 0° for an additionalhour the reaction was poured into ice water and partitioned. The aqueouslayer was extracted once with methylene chloride and the combinedorganic layers were washed with cold 1.5N aqueous sodium hydroxide.Drying over magnesium sulfate followed by solvent removal gave a paleyellow oil, which was purified by short path distillation at 0.2 torr.The o-bromocinnamyl bromide was distilled at 105° and 37.3 g (85% yield)was isolated. NMR (CDCl₃): δ 6.8-7.7 (m; 5H); 6.33 (AB: 1H); 4.15 (d;2H).

Step C: Preparation of6-(o-bromocinnamyl)-2,3-dihydro-5-hydroxybenzofuran

Sodium hydride (0.72 g; 18 mM, 60% in mineral oil) was washed twice withhexane under a stream of nitrogen. It was then suspended in 25 ml ofanhydrous benzene in a 250 ml side-arm round bottom flask equipped witha dropping funnel. The 5-hydroxy-2,3-dihydrobenzofuran was added in oneportion (1.63 g; 12.0 mM) i 40 ml of benzene under positive nitrogenpressure and the resulting suspension was stirred at room temperaturefor 45 minutes. o-Bromocinnamyl bromide was then added in 15 ml ofbenzene. No reaction was observed at R.T. or at 50° so the reaction washeated to 75° for two hours at which time the reaction was cooled to 23°and poured into dilute hydrochloric acid solution. This was extracted 3times with ether, dried over magnesium sulfate, and stripped to a brownoil. This crude material was purified by chromatography on a Waters'Prep 500 equipped with one cartridge and eluted and recycled with 20%ethyl acetate in hexane. Recrystallization from ethyl acetate/hexanegave 1.58 g (40%) of tan crystals identified spectrally as6-(o-bromocinnamyl)-2,3-dihydro-5-hydroxybenzofuran.

NMR (CDCl₃): δ6.6-7.4 (m; 4H); 6.4-6.6 (m; 3H); 6.08 (dqt (16 Hz and 6Hz); 1H); 4.67 (s; 1H); 4.40 (t(8 Hz); 2H); 3.43 (d(6 Hz); 2H); 3.03(t(8 Hz); 2H).

IR: 3700, 3500, 2950, 1480, 1430, 1330, 1280, 1160, 1140, 1020, 980,965, 945, 865 cm⁻¹ (CHCl₃).

    ______________________________________                                        Microanalysis:                                                                             C           H      Br                                            ______________________________________                                        Calculated:  61.65       4.57   24.13                                         Found:       61.73       4.53   23.88                                         ______________________________________                                    

EXAMPLE 3 6-(o-cyanocinnamyl)-2,3-dihydro-5-hydroxy-benzofuran

6-(o-Bromocinnamyl)-2,3-dihydro-5-hydroxybenzofuran (1.49 g; 4.5 mM) andcuprous cyanide (1.37 g; 15.3 mM) were suspended in 18 ml of anhydrousN-methyl-2-pyrrolidinone. Nitrogen was bubbled through this suspensionfor approximately 15 minutes and the reaction mixture was then heated to175° under nitrogen for 2 hours. After cooling to ambient temperaturethe reaction was poured into 60 ml of water containing 60 ml ofconcentrated ammonium hydroxide. This emulsion was extracted three timeswith ether, dried over magnesium sulfate and stripped to a brown oil.Flash chromatography of this material on a 30 mm by 51/2" column ofsilica gel eluted with 500 ml of 35% ethyl acetate in hexane gave asolid which was recrystallized from ethyl acetate/hexane producing 0.95g (76%) of white crystals identified as6-(o-cyanocinnamyl)-2,3-dihydro-5-hydroxy-benzofuran.

NMR (CDCl₃): δ 7.2-7.6 (m; 4H); 6.2-6.8 (m; 4H); 4.60 (s; 1H); 4.43 (t(9Hz); 2H); 3.50 (d(6 Hz); 2H); 3.07 (t(9 Hz); 2H).

IR: 3700, 3450, 2900, 2250, 1600, 1470, 1420, 1150, 1140, 980, 960, 940,900, 860 cm⁻¹.

    ______________________________________                                        Microanalysis:                                                                             C           H      N                                             ______________________________________                                        Calculated:  77.96       5.45   5.05                                          Found:       77.67       5.28   4.83                                          ______________________________________                                    

m.p.=137°-9°.

EXAMPLE 4 2,3-dihydro-5-hydroxy-6-(o-hydroxymethylcinnamyl)benzofuran

A round bottom flask, equipped with a dropping funnel, was flame-driedunder nitrogen and charged with 23 ml of anhydrous benzene and6-(o-cyanocinnamyl)-2,3-dihydro-5-hydroxybenzofuran (0.85 g; 3.1 mM).This solution was chilled in an ice bath and 4.5 ml (6.9 mM) ofdiisobutylaluminum hydride in toluene was added dropwise. The reactionwas stirred at 0° for one hour and then poured into 1N aqueoushydrochloric acid. This resulted in an emulsion which was filteredthrough celite and partitioned. The aqueous phase was extracted withether and the combined organic layers were dried over magnesium sulfate.The suspension was filtered and stripped of solvent in vacuo. Theresultant brown solid was taken up in 75 ml of methanol and sodiumborohydride (170 mgs) was added in portions with the usual gasevolution. The reaction was stirred at room temperature for 30 minutesand the solvent was then removed at reduced pressure. The resulting oilwas purified by flash chromatography on a 30 mm by 51/2" column ofsilica gel eluted with 600 ml of 30% ethyl acetate in hexane. This gaveonly 106 mg (13%) of2,3-dihydro-5-hydroxy-6-(o-hydroxymethylcinnamyl)-benzofuran.

NMR (CDCl₃): δ8.17 (s; 1H); 6.9-7.3 (m; 4H); 6.64 (d(15 Hz); 1H); 6.63(s; 1H); (CDCl₃ /DMSO-D₆) 6.33 (s; 1H); 6.13 (d of t (15 Hz and 7 Hz);1H); 4.42 (s; 2H); 4.36 (t(8 Hz); 2H); 3.40 (d(7 Hz); 2H); 3.03 (t(8Hz); 2H); 2.98 (s; 1H).

EXAMPLE 5 5-cinnamyl-2,3-dihydro-6-hydroxybenzopyran Step A: Preparationof p-propargyloxyphenol

Hydroquinone (49.6 g; 450 mM) was dissolved in 700 ml of anhydrousacetone in a two liter, 3-necked, round bottom flask equipped withreflux condensor, air stirrer and nitrogen bubbler. Potassium carbonate(65.6 g; 460 mM) was ground finely and then added to the reactionfollowed by propargylbromide (53.6 g; 450 mM). The reaction was heatedat reflux for three days, cooled to room temperature, filtered and thesolvent removed. The residue was taken up in ether and extracted threetimes with 2.5N aqueous sodium hydroxide. The basic layers wereacidified with concentrated hydrochloric acid while adding ice andextracted twice with ether. The combined ethereal layers were dried overmagnesium sulfate, charcoal was added, and the mixture was filteredthrough celite. The solvent was removed in vacuo and the remaining darkbrown sludge was purified by chromatography in two portions on a WatersPrep 500 equipped with two silica gel cartridges and eluted with 20%ethyl acetate in hexane after injecting in ether solution. This produced21.4 g (64% of theory) of the desired p-propargyloxyphenol.

NMR (CDCl₃): δ 6.5-6.8 (m; 4H); 5.53 (s; 1H); 4.50 (d(2 Hz); 2H); 2.40(t(2 Hz); 1H).

Step B: Preparation of 6-hydroxybenzopyran

Nitrogen was bubbled through 100 ml of diethylaniline for 15 minutes and5.0 g (34 mM) of p-propargyloxyphenol was added in one portion. Thereaction mixture was heated to 200° under nitrogen overnight. The brownsolution was poured into 600 ml of ether and extracted twice with 2.5Naqueous sodium hydroxide. The combined aqueous layers were extractedonce with ether and then acidified with concentrated hydrochloric acidat 0°. The acidic phase was extracted twice with ether. The etherextracts were dried over magnesium sulfate, decolorized with charcoal,and filtered through celite. Solvent removal in vacuo gave areddish-brown oil which was purified by flash chromatography on a 30 mmby 51/2" column of silica gel eluted with 600 ml of 20% ethyl acetate inhexane. This produced 2.96 g (59%) of 6-hydroxybenzopyran as a yellowoil.

NMR (CDCl₃): δ 6.0-6.8 (m; 4H); 5.5-5.8 (do(t(11 Hz and 4 Hz); 1H); 5.45(s; 1H); 4.63 (d of t(4 Hz and 2 Hz); 1H).

IR: 3750, 3450, 2900, 1640, 1580, 1490, 1450, 1370, 1280, 1160, 1140,1110, 1030, 1015, 942, 920, 840, 830 cm⁻¹.

Step C: Preparation of 2,3-dihydro-6-hydroxybenzopyran

The 6-hydroxybenzopyran (1.5 g; 10 mM) was dissolved in 100 ml ofanhydrous benzene along with Wilkinson's catalyst (280 mgs; 0.30 mM).This hydrogenation bottle containing this reaction mixture was firstflushed with nitrogen and then with hydrogen. The bottle was pressurizedto 40 psi in a Parr shaker and agitated for 40 minutes at which time thepressure in the bottle (400 ml dead volume) had dropeed to 30 psi andwas dropping no further. The bottle was then flushed with nitrogen andthe solvent was removed in vacuo. The residue was taken up in ether andfiltered through a pad of celite. The solvent was removed and the oilwas purified by flash chromtography on a 30 mm×6" column of silica geleluted with 600 ml of 20% ethyl acetate in hexane. This purificationproduced 1.40 g (93%) of 2,3-dihydro-6-hydroxybenzopyran as a whitecrystalline solid.

NMR (CDCl₃): δ 6.3-6.6 (m; 3H); 5.43 (s; 1H); 4.00 (brt(5 Hz); 2H); 2.69(brt(6 Hz); 2H); 1.7-2.0 (m; 2H).

Step D: Preparation of 7-cinnamyl-2,3-dihydro-6-hydroxybenzopyran

Sodium hydride (0.56 g; 14 mM; 60% in mineral oil) was washed twice withhexane under a stream of nitrogen. It was suspended in 20 ml ofanhydrous benzene under a positive pressure of nitrogen and the2,3-dihydro-6-hydroxybenzopyran (1.40 g; 9.3 mM) was added rapidlydropwise in 30 ml of benzene. This suspension was stirred for one hourat room temperature and then a solution of cinnamyl bromide (2.06 g:10.5 mM) in 15 ml of benzene was added dropwise. After stirring for 2hours at ambient temperature the reaction mixture was poured into 1Naqueous hydrochloric acid and partitioned. The aqueous layer wasextracted once with ether and the combined organic layers were driedover magnesium sulfate, filtered through a fritted funnel, and strippedof solvent in vacuo. The resulting oil was purified by chromatographytwice on the Waters' Prep 500 equipped with one cartridge and elutedfirst with 15% ethyl acetate in hexane and then with 8% ethyl acetate inhexane with recycling. This produced the two possible cinnamyl alkylatedregioisomers, the less polar oil (400 mgs) showed two ortho protons onthe benzopyran ring in the NMR. The major product,7-cinnamyl-2,3-dihydro-6-hydroxybenzopyran, was isolated in 20% (500 mg)and crystallized to a yellow solid.

(a) The 5-cinnamylisomer:

NMR: (DMSO-D₆) δ 8.67 (s; 1H); 7.0-7.4 (m; 5H); 6.55 (d(9 Hz); 1H); 6.39(d(9 Hz); 1H); 6.26 (s; 2H); 3.92 (brt(6 Hz); 2H); 3.33 (brd(8 Hz); 2H);2.65 (d(t(6 Hz); 2H); 1.6-2.0 (m; 2H).

IR: 3700, 3450, 3000, 2900, 1600, 1475, 1250, 1170, 1090, 1070, 970, 910cm⁻¹ (CHCl₃).

MS: 266 (M+, 66%); 162 (100%); 91 (53%).

    ______________________________________                                        Microanalysis:     C      H                                                   ______________________________________                                        Calculated:        81.17  6.81                                                Found:             80.14  7.01                                                ______________________________________                                    

(b) The 7-cinnamylisomer

NMR: (CDCl₃) δ7.0-7.3 (m; 5H); 6.1-6.5 (m; 4H); 4.59 (brs; 1H); 4.02(brt(5 Hz); 2H); 3.39 (d(4 Hz); 2H); 2.22 (brt(6 Hz); 2H); 1.8-2.1 (m;2H). (CHCl₃) IR: 3800, 3600, 3000, 2900, 1600, 1490, 1420, 1330, 1250,1150, 1100, 1060, 980, 965, 943, 889 cm⁻¹.

MS: 266 (M+, 66%); 162 (100%); 91 (43%).

    ______________________________________                                        Microanalysis:     C      H                                                   ______________________________________                                        Calculated:        81.17  6.81                                                Found:             80.67  6.87                                                ______________________________________                                    

m.p.=99°-101°.

EXAMPLE 6 7-(o-bromocinnamyl)-2,3-dihydro-6-hydroxybenzopyran

Sodium hydride (1.36 g; 34 mM; 60% in mineral oil) was washed twice withhexane under a stream of nitrogen. It was suspended in 50 ml ofanhydrous benzene in a 3-necked 500 ml flask equipped with a droppingfunnel. To this suspension benzene (75 ml) containing 6-hydroxydihydrobenzopyran (3.4 g; 22.7 mM) was added. The resulting reactionmixture was stirred at room temperature for about 40 minutes and anadditional 30 ml of benzene containing o-bromocinnamyl bromide (7.28 g;28.4 mM) was added dropwise. This reaction was heated to reflux for 1.5hours and cooled to ambient temperature. The suspension was poured into150 ml of cold aqueous 1N hydrochloric acid, partitioned, and theaqueous layers was extracted once with ether. The combined organicphases were dried over magnesium sulfate and stripped of solvent. Theresulting oil was chromatographed twice on the Waters Prep 500 equippedwith one cartridge. The first elution with 15% ethyl acetate in hexaneremoved most of the impurities and the mixture of regioisomers obtainedwas separated by eluting again with 15% ethyl acetate in hexane withthree recycles on one column. The less polar component (1.0 g; tansolid) was 5-(o-bromocinnamyl)isomer and the most polar component (1.04g; recrystallized from ethyl acetate/hexane) was7-(o-bromocinnamyl)-2-3-dihydro-6-hydroxybenzopyran.

(a) 5-(o-bromocinnamyl)-isomer

NMR (CDCl₃): δ6.7-7.5 (m; 4H); 7.11 (d(15 Hz); 1H); 6.53 (s; 1H); 6.40(s; 1H); 6.15 (d of t (15 Hz and 6 Hz); 1H); 4.67 (brs; 1H); 4.04 (t(5Hz); 2H); 3.43 (d(6 Hz); 2H); 2.63 (t(7 Hz); 2H); 1.90 (m; 2H).

(b) 7-(o-bromocinnamyl)-isomer

NMR (CDCl₃): δ6.8-7.4 (m; 4H); 6.50 (brs; 3H); 6.05 (d of t (15 Hz and 6Hz); 1H); 4.60 (s; 1H); 4.03 (brt; 2H); 3.46 (d(6 Hz); 2H); 2H); 2.73(brt; 2H); 1.8-2.1 (m; 2H).

EXAMPLE 7 2-(m-Methoxycinnamyl)-4-methoxyphenol Step A: Preparation ofmethyl m-methoxycinnamate

Anhydrous methanol (400 ml) was chilled to 0° and treated with acetylchloride (20 ml) to give a 3% solution of methanolic HCl.m-Methoxycinnamic acid (14.24 g; 80 mM) was added to this solution inone portion and stirred until dissolution was obtained. The reactionmixture was then allowed to stand at ambient temperature overnight. Thesolvent was removed in vacuo at 35° and the resulting oil was filteredthrough a one inch pad of silica gel in a 150 ml fritted funnel with 400ml of a 35% solution of ethyl acetate in hexane. The solvent was thenremoved in vacuo leaving 14.5 grams of methyl m-methoxycinnamate as anoil.

NMR (CDCl₃): δ 7.63 (d(16 Hz); 1H); 6.7-7.3 (m; 4H); 6.36 (d(16 Hz);1H); 3.77 (s; 6H).

Step B: Preparation of m-methoxy-cinnamyl alcohol

The methyl m-methoxycinnamate was taken up in 50 ml of anhydrous tolueneand chilled to -70° under nitrogen. Diisobutylaluminum hydride (54 ml;83 mM; 1.54M in toluene) was added dropwise through a side-arm additionfunnel. Some starting material remained as detected by TLC (35% ethylacetate/hexane on silica gel) so a further 15 ml of diisobutylaluminumhydride was added. The reaction was allowed to warm to room temperatureand then carefully quenched with water at 0° giving an emulsion. Theemulsion was taken up in cold 2N aqueous hydrochloric acid andpartitioned. The aqueous layer was extracted twice with ether and thecombined organic layers were washed with 2.5N aqueous sodium hydroxideand with brine. The organic extracts were then dried over K₂ CO₃ andstripped of volatiles in vacuo. The clear oil was chromatographed on onecartridge in a Water's Prep 500 with 35% ethyl acetate in hexane to give9.38 g (71% yield) of m-methoxycinnamyl alcohol.

NMR (CDCl₃): δ6-7.4 (m; 6H); 4.28 (d(4 Hz); 2H); 3.70 (s; 3H); 1.90 (br;1H).

Step C: Preparation of m-methoxycinnamylbromide

Pyridinium hydrobromide perbromide (5.00 g; 12.5 mM; 80%) was suspendedin 25 ml of chloroform under nitrogen and hexamethyldisilane was addedin one portion giving rise to a slightly exothermic reaction. Thesuspension was chilled to 0° and m-methoxycinnamyl alcohol (1.64 g; 10.0mM) was slowly added dropwise in 4 ml of chloroform. The reaction wasstirred for an additional 30 minutes at 0° and then poured into 50 ml ofanhydrous ether. This suspension was washed three times with water anddried over magnesium sulfate. Removal of the solvent under vacuum gave awhite solid which was taken up in hexane and filtered through a frittedfunnel. The white solid (1.56 g) proved to be simple bromine additionacross the double bond. Removal of the hexane from the filtrate gave anoil (1.2 g; 53%) which NMR indicated to be the desired m-methoxycinnamylbromide. NMR (CDCl₃); δ 6.6-7.6 (m; 4H); 6.1-6.6 (m; 2H); 4.30 (d, 6 Hz;2H); 3.75 (s, 3H).

Step D: Preparation of 2-(m-methoxycinnamyl)-4-methoxyphenol

Sodium hydride (0.40 g; 10.0 mM; 60% in mineral oil) was washed twicewith hexane under a stream of nitrogen. The hydride was then suspendedin 8 ml of anhydrous benzene and p-methoxyphenol (0.62 g; 5.0 mM) wasadded in one portion. After stirring at room temperature for fifteenminutes benzene (8 ml) was added containing m-methoxycinnamyl bromide(5.3 mM). The reaction was heated to reflux overnight under an aircondenser and quenched by pouring into 1N aqueous hydrochloric acid.This was extracted with ether, dried over magnesium sulfate and strippedin vacuo. In an attempt to remove the starting p-methoxyphenol theresulting brown oil was taken up in ethyl acetate/hexane and washedeight times with water. Drying and solvent removal was followed by flashchromatography on a 30 mm×71/2" column of silica gel eluted with 700 mlof 20% ethyl acetate in hexane. This produced a yellow oil (400 mg; 30%)identified by NMR as 2-(m-methoxycinnamyl)-4-methoxyphenol.

IR: 3400, 3000 2880, 1620, 1600, 1510, 1450, 1250, 1050, 990, 880, 790,700 cm⁻¹.

EXAMPLE 8 2-(o-Bromocinnamyl)-4-methoxyphenol Step A: Preparation ofethyl o-bromocinnamate

Carboethoxymethylidene triphenylphosphorane (94 g, 270 mM) was dissolvedin 350 ml of methylenechloride under nitrogen. o-Bromobenzaldehyde (31.5ml; 270 mM) was added via an addition funnel in 125 ml of methylenechloride. The solution was allowed to stand at room temperatureovernight and then the solvent was removed in vacuo. The slushy residuewas taken up in 10% ethyl acetate in hexane and filtered through aone-inch pad of silica gel in a 350 ml fritted funnel with one liter of10% ethyl acetate in hexane. Solvent removal on the rotary evaporatorfollowed by pumping overnight gave 66.3 g of an oil, ethylo-bromocinnamate in 96% yield. The NMR indicates a 4.5 to 1 mixture oftrans to cis isomers. NMR:

trans: 7.95 (d (16 Hz); 1H); 7.0-7.7 (m, 4H); 6.3 (d (16 Hz); 1H); 4.15(q 6 Hz); 2H); 1.34 (t (7 Hz); 3H).

cis: 5.987 (d (12 Hz)).

Step B: Preparation of 2-(o-bromocinnamyl)-4-methoxyphenol

Sodium hydride (1.68 g; 42 mM; 60% in mineral oil) was washed twice withhexane under a stream of nitrogen. It was then suspended in 75 ml ofbenzene and another 75 ml of benzene containing p-methoxyphenol (4.45 g;36 mM) was added dropwise at room temperature. The suspension wasstirred for an additional 45 minutes and then 30 ml of benzenecontaining o-bromocinnamyl bromide (38 mM) was added dropwise. Thereaction was heated to 50° under nitrogen for two hours and then cooledto ambient temperature. The quench was accomplished by pouring thereaction into cold dilute hydrochloric acid. The layers were separatedand the aqueous phase was extracted once with benzene. The combinedorganic layers were extracted ten times with water in an effort toremove the p-methoxyphenol and were then dried over magnesium sulfateand stripped of solvent. The resulting oil was purified bychromatography on a Waters Prep 500 equipped with two cartridges andeluted with 20% ethyl acetate in hexane. The2-(o-bromocinnamyl)-4-methoxyphenol (8.25 g) was isolated as a paleyellow oil in 68% yield.

NMR (CDCl₃): δ6.6-7.6 (m; 8H); 6.2 (d of t (16 Hz and 6 Hz); 1H); 4.70(s; 1H); 3.73 (s; 3H); 3.55 (br d (6 Hz); 2H).

IR: 3500, 1500, 1430, 1200, 1030, 965 cm⁻¹.

EXAMPLE 9 2-(o-Cyanocinnamyl)-4-methoxyphenol

Cuprous cyanide (1.03 g; 11.5 mM) and2-(o-bromocinnamyl)-4-methoxyphenol (1.03 g; 3.23 mM) were combined in12 ml of anhydrous N-methylpyrrolidinone. Nitrogen was bubbled throughthe resulting suspension for five minutes and it was then heated to 175°under positive nitrogen pressure for 2 hours. The reaction was pouredinto 50 ml of conc. NH₄ OH and 50 ml of water. The emulsion wasextracted three times with ether and the ether extracts were washed oncewith water. Drying over magnesium sulfate was followed by solventremoval leaving a brown oil. This crude product was purified by flashchromatography with 35% ethyl acetate in hexane on a 30 mm×6" column ofsilica gel. Recrystallization from ethyl acetate/hexane gave2-(o-cyanocinnamyl)-4-methoxyphenol as a tan solid (335 mg, 39% yield)m.p. 72°-74°.

NMR (CDCl₃): δ6.4-7.6 (m; 9H); 3.7 (s; 3H); 3.57 (d (5 Hz); 2H).

IR: 3620, 3350, 2975, 2870, 2250, 1600, 1500, 1440, 1180, 975 cm⁻¹.

MS: 265 (M⁺) (100); 149 (36); 136 (48).

    ______________________________________                                        Micro analysis:                                                                            C           H      N                                             ______________________________________                                        Calc'd.      76.96       5.70   5.28                                          Found:       76.69       5.70   5.37                                          ______________________________________                                    

EXAMPLE 10 2-(o-Formylcinnamyl)-4-methoxyphenol

A flame-dried flask was charged with 2-(o-cyanocinnamyl)-4-methoxyphenol(1.86 g; 7.0 mM) and 50 ml of anhydrous benzene under nitrogen. Thesolution was cooled to 0° and a toluene solution of diisobutylaluminumhydride (10.5 ml; 16 mM; 1.53M) was added dropwise via an additionfunnel. After 2 hours at 0° a further 5 ml of diisobutylaluminum hydridewas added. A small aliquot was worked up at this time and the 1R showedthe loss of the nitrile absorption of 2250 cm⁻¹ and the appearance of acarbonyl stretch at 1700 cm⁻¹. The reaction was poured into cold dilutehydrochloric acid solution and partitioned. The organic phase was washedwith water and dried over magnesium sulfate. Solvent removal in vacuoleft a brown oil which was chromatographed on the Waters Prep 500equipped with two cartridges and eluted with 35% ethyl acetate inhexane. This gave 0.50 g (27%) of 2-(o-formylcinnamyl)-4-methoxyphenolas an oil.

NMR (CDCl₃): δ10.23 (s; 1H); 7.0-7.8 (m; 6H); 6.6-6.9 (m; 3H); 6.20 (dof t (15 Hz and 6 Hz); 1H); 5.4-5.6 (br s; 1H); 3.73 (s; 3H); 3.55 (d (6Hz); 2H).

IR: cm⁻¹ 3350, 2900, 2800, 2700, 1740, 1580, 1480, 1412, 1190, 1020,950, 790, 730.

EXAMPLE 11 2-(o-Hydroxymethylcinnamyl)-4-methoxyphenol

Sodium borohydride (35 mg) was added in one portion to a solution of2-(o-formylcinnamyl)-4-methoxyphenol (240 mg; 0.89 mM) in 5 ml ofmethanol. The reaction was stirred at room temperature for 2 hours andthen the solution was removed in vacuo. The residue was taken up in 2Naqueous hydrochloric acid and extracted with ether. The ethereal phasewas washed with water, dried over magnesium sulfate, stripped ofsolvent, and filtered through 11/2" of silica gel in a 30 ml frittedfunnel with 100 ml of 50% ethyl acetate/hexane providing 240 mg (99%) ofpure 2-(o-hydroxymethylcinnamyl)-4-methoxyphenol.

NMR (CDCl₃): 7.0-7.4 (m; 4H); 6.4-6.8 (m; 4H); 6.10 (d of t (15 Hz and 6Hz); 1H); 4.60 (s; 2H); 3.67 (s; 3H); 3.45 (d (6 Hz); 2H).

IR: 3400, 1400, 1230, 1050, 980, 770 (Nujol).

MS: 270 (M⁺, 6%); 252 (32%); 137 (100%); 136 (30%); 116 (30%).

    ______________________________________                                        Micro analysis:    C      H                                                   ______________________________________                                        Calc'd.            75.53  6.71                                                Found:             74.77  6.78                                                ______________________________________                                    

m.p.=101°-102°.

EXAMPLE 12 2-(p-Fluorocinnamyl)-4-methoxyphenol

Sodium hydride (0.94 g; 23.5 mM; 60% in mineral oil) was washed twicewith hexane under nitrogen in a flame-dried, three-necked,round-bottomed flask. The sodium hydride was then suspended in 35 ml ofbenzene and 35 ml more of benzene containing p-methoxyphenol (2.48 g; 20mM) were added. After stirring for 45 minutes at room temperature,p-fluorocinnamyl bromide (4.3 g; 20 mM) was added dropwise in 30 ml ofbenzene. The reaction mixture was heated to reflux for 20 minutes andthen poured into cold 1N aqueous hydrochloric acid. The layers wereseparated an the aqueous layer was extracted once with benzene. Thecombined benzene layers were washed five times with water, dried overmagnesium sulfate and stripped of solvent leaving a brown residue. Thisoil was crystallized twice from hexane producing 2.21 g (43%) of tancrystals of 2-(p-fluorocinnamyl)-4-methoxyphenol.

NMR (CDCl₃): δ5.9-7.3 (m; 9H); 4.52 (s; 1H); 3.70 (s; 3H); 3.45 (d (6Hz); 2H).

IR: 3570, 3500, 3420, 2880, 2805, 1590, 1415, 1140, 1080, 1020, 960cm⁻¹.

MS: 258 (M⁺) (59%); 149 (31%); 136 (100%); 109 (54%); 108 (38%).

    ______________________________________                                        Micro analysis:                                                                            C           H      F                                             ______________________________________                                        Calc'd.      74.40       5.85   7.36                                          Found:       74.51       5.93   7.39                                          ______________________________________                                    

m.p.=79°-81°.

EXAMPLE 13 2-(o-Fluorocinnamyl)-4-methoxyphenol

Sodium hydride (1.88 g, 47 mM; 60% in mineral oil) was washed twice withhexane under a stream of nitrogen and then suspended in 75 ml of benzenein a flame-dried flask. To this suspension was added 75 ml of anhydrousbenzene containing p-methoxyphenol (4.96 g; 40 mM). The deprotectionreaction was stirred at room temperature for one hour at which time 30ml of benzene containing o-fluorocinnamyl bromide (8.60 g; 40 mM) wasadded. No reaction occurred at room temperature so the mixture washeated to reflux for ten minutes. The suspension was then cooled, pouredinto 1N aqueous hydrochloric acid and partitioned. The aqueous layer wasextracted once with benzene and the combined organic layers were washedfive times with water. After drying over magnesium sulfate the solventwas removed and the residue was chromatographed on a Waters Prep 500equipped with two cartridges and eluted with 20% ethyl acetate inhexane. This produced a brown oil which was seen to be analytically pure2-(o-fluorocinnamyl)-4-methoxyphenol in 64% yield (6.56 g).

NMR (CDCl₃): δ6.15-7.40 (m; 9H); 4.6-4.8 (br s; 1H); 3.66 (s; 3H); 3.47(d (6 Hz); 2H).

IR: 3350, 3000, 2900, 2800, 1600, 1480, 1440, 1240, 1210, 1185, 1080,1020, 960, 780, 740 cm⁻¹.

MS: 258 (M⁺) (94%); 149 (48%); 136 (100%); 121 (28%); 109 (53%).

    ______________________________________                                        Micro analysis:                                                                            C           H      F                                             ______________________________________                                        Calc'd.      74.40       5.85   7.36                                          Found:       74.08       5.85   7.50                                          ______________________________________                                    

EXAMPLE 142-Ethoxycarbonyl-1-methyl-4-(2-hydroxy-5-methoxyphenyl)propenylpyrroleStep A: Preparation of 2-Ethenyl-4-methoxy-1-O-methoxymethylphenol

To a suspension of 104 g (0.291 moles) of methyltriphenylphosphoniumbromide in 100 ml dry tetrahydrofuran at 0° was added 115 ml (0.275moles) of 2.4M n-butyllithium and the dark red solution was stirred at0° for 30 minutes. Then a solution of 38.2 g (0.195 moles) of2-(3-oxapropyloxy)-5-methoxybenzaldehyde in 100 ml of drytetrahydrofuran was added and the solution was stirred at roomtemperature for 60 minutes. The solution was concentrated and theresidue partitioned between ether and water. The ether layer was washedwith aqueous Na₂ CO₃, then brine, then dried (Na₂ SO₄) and concentrated.The oily residue was dissolved in 500 ml of 10% ethylacetate-hexane andcooled at 0° overnight, then filtered. The filtrate was concentrated togive 33.8 g (89%) of 2-ethenyl-4-methoxy-1-O-methoxymethylphenol as apale yellow liquid. NMR (CDCl₃) δ3.45 (s, 3H), 3.71 (s, 3H), 5.10 (s,2H), 5.20 (d of d, 1H), 5.6 (d of d, 1H), 6.5-7.0 (m, 4H).

Step B: Preparation of2-(2-Hydroxyethyl)-4-methoxy-1-O-methoxymethylphenol

To a solution of 33.8 g (0.174 moles) of2-ethenyl-4-methoxy-1-O-methoxymethylphenol in 300 ml of drytetrahydrofuran at 0° was added 120 ml of a 1.0M borane-tetrahydrofuransolution. The solution was stirred at room temperature for 60 minutes,cooled to 0° and 48 ml of 10% NaOH was added dropwise. Then 41 ml of 30%H₂ O₂ was added with caution and the mixture was stirred at roomtemperature for 30 minutes. The solution was partitioned between etherand water and the ether layer was washed with aqueous NaHCO₃ and brine,dried (Na₂ SO₄) and evaporated. The oily residue was purified by Prep.500 HPLC using 40% ethylacetatehexane to afford 27.3 g (73%) of2-(2-hydroxyethyl)-4-methoxy-1-O-methoxymethylphenol as a colorlessliquid. NMR (CDCl₃) δ2.15 (s, br, 1H, --OH), 2.8 (t, 2 H, J=7 Hz), 3.40(s, 3H), 3.65 (s, 3H), 3.73 (m, 2H), 5.05 (s, 2H), 6.55 (d of d, 1H),6.61 (s, 1H), 6.88 (d, 1H).

Step C: Preparation of 2-(2-Iodoethyl)-4-methoxy-1-O-methoxymethylphenol

A solution of 27.3 g (0.129 moles) of2-(2-hydroxyethyl)-4-methoxy-1-O-methoxymethylphenol, 16 ml pyridine and15.5 ml (22.9 g, 0.200 moles) in 200 ml of dichloromethane was stirredat 0° for 60 minutes. The solution was partitioned betweendichloromethane and water and the organic layer was washed with aqueousNaHCO₃ and brine and then dried (Na₂ SO₄) and evaporated.

The residue was dissolved in 300 ml of acetone and to this was added asolution of 96 g (0.640 moles) of NaI in 600 ml acetone. The solutionwas heated at 60° for 3 hours under N₂, then concentrated, partitionedbetween ether and water. The ether layer was washed with aqueous Na₂ S₂O₇, then brine, dried (Na₂ SO₄) and evaporated. The oily residue waschromatographed on a Prep. 500 HPLC using 5% ethyl acetate-hexane toafford 38.1 g (92%) of 2-(2-iodoethyl)-4-methoxy-1-O-methoxymethylphenolas a colorless liquid. NMR (CDCl₃) δ3.25 (m, 4H), 3.50 (s, 3H), 3.75 (s,3H), 5.10 (s, 2H), 6.6-6.7 (m, 2H), 6.95 (d, 1H).

Step D: Preparation of2-[2-(3-oxapropyloxy)-5-methoxyphenyl]ethyltriphenyl phosphonium iodide

A mixture of 38.1 g (0.118 moles) of2-(2-iodoethyl)-4-methoxy-1-O-methoxymethylphenol and 38.1 g (0.145moles) of triphenylphosphine was heated neat at 160° C. After 60 minutesthe solution was cooled and the glassy residue was crystallized from CH₂Cl₂ -toluene to afford 47.3 g (69%) of2-[2-(3-oxapropyloxy)-5-methoxyphenyl]ethyltriphenyl phosphonium iodideas a white powder. NMR (CDCl₃) δ3.0 (m, 2H), 3.40 (s, 3H), 3.75 (m, 5H),5.05 (s, 2H), 6.60 (d of d, 1H, J=7.5, J=2), 6.90 (d, 1H, J=7) 6.98 (d,1H, J=2), 7.70 (s, 15H).

Step E: Preparation of2-Ethoxycarbonyl-1-methyl-4-[2-(3-oxapropyloxy)-5-methoxyphenyl]propenylpyrrole

A solution of 1.6M n-butyllithium (4.0 ml, 6.0 mmol) was added to asuspension of 3.45 g (5.90 mmol) of2-[2-(3-oxapropyloxy)-5-methoxyphenyl]ethyltriphenylphosphonium iodidein 20 ml of dry tetrahydrofuran at 0°. After 30 minutes a solution of1.10 g (6.07 mmol) of 2-ethoxycarbonyl-1-methylpyrrole-2-carboxaldehydein 5 ml of dry tetrahydrofuran was added and the solution was stirredfor 30 minutes. The mixture was partitioned between ether and water andthe ether layer was washed with water, dried (Na₂ SO₄) and evaporated.The residue was chromatographed on silica using 20% ethylacetatehexaneto afford 1.78 g (85%) of2-ethoxycarbonyl-1-methyl-4-[2-(3-oxapropyloxy)-5-methoxyphenyl]propenylpyrroleas a colorless glass. NMR (CDCl₃) δ1.30 (t, 3H, J=6 Hz), 3.40 (s, 3H),3.45 (trans), 3.70 (cis) (d, J=6 Hz, total 2H, cis:trans, 1:10), 3.78(s, 3H), 3.90 (s, 3H), 4.25 (q, 2H, J=6 Hz), 5.0 (trans), 5.05 (cis) (s,total 2H), 5.75-6.6 (m, 2H), 6.7-7.3 (m, 5H).

Step F: Preparation of2-Ethoxycarbonyl-1-methyl-4-(2-hydroxy-5-methoxyphenyl)propenylpyrrole

A solution of 1.00 g (2.79 mmol) of2-ethoxycarbonyl-1-methyl-4-[2-(3-oxapropyloxy)-5-methoxyphenyl]propenylpyrrolein 5 ml of 1:1 aqueous trifluoroacetic acid was stirred at 0° for 1hour, then at room temperature for 1 hour. The solution was partitionedbetween ether and water and the ether layer was washed with 3 portionsof water. The ether extract was dried (Na₂ SO₄), concentrated, andchromatographed on silica using 20% ethylacetatehexane to afford 0.68 g(77%)2-ethoxycarbonyl-1-methyl-4-(2-hydroxy-5-methoxyphenyl)propenylpyrroleof a colorless glass. NMR (CDCl₃) δ1.30 (t, 3H, J=6 Hz), 3.4 (trans),3.65 (cis) (d, total 2H, J=6 Hz, trans:cis=10:1), 3.78 (s, 3H), 3.90 (s,3H), 4.25 (q, 2H, J=6 Hz), 5.75-6.6 (m, 2H), 6.7-7.3 (m, 5H).

EXAMPLE 152-Ethoxycarbonyl-(1-methyl-5-[2-(3-oxapropyloxy)-5-methoxyphenyl]propenylpyrroleStep A: Preparation of2-Ethoxycarbonyl-1-methyl-5-[2-(3-oxapropyloxy)-5-methoxyphenyl]propenylpyrrole

From 1.1 g (6.07 mmol)2-ethoxycarbonyl-1-methylpyrrole-5-carboxaldehyde, there was preparedaccording to the procedures described in Step E of Example 14 1.47 g(69%) of2-ethoxycarbonyl-1-methyl-5-[2-(3-oxapropyloxy)-5-methoxyphenyl]propenylpyrroleas a colorless glass. NMR (CDCl₃) δ1.30 (t, 3H, J=6 Hz), 3.40 (s, 3H),3.45 (trans), 3.70 (cis) (d, 2H, J=6 Hz, trans:cis=8:1), 3.80 (s, 3H),4.20 (s, 3H), 4.30 (q, 2H, J=6 Hz), 5.1 (trans), 5.15 (cis) (s, 2H),5.8-6.6 (m, 2H), 6.7-7.1 (m, 5).

Step B: Preparation of2-Ethoxycarbonyl-1-methyl-5-(2-hydroxy-5-methoxyphenyl)propenylpyrrole

From 1.0 g of2-ethoxycarbonyl-1-methyl-5-[2-(3-oxapropyloxy)-5-methoxyphenyl]propenylpyrrole,there was prepared, by the procedures described in Step F of Example 14,0.74 g (84%) of2-ethoxycarbonyl-1-methyl-5-(2-hydroxy-5-methoxyphenyl)propenylpyrroleas a colorless glass. NMR (CDCl₃) δ1.30 (t, 3H, J=6 Hz), 3.45 (trans),3.70 (cis) (d, J=6 Hz, 2H), trans:cis=8:1, 3.80 (s, 3H), 4.20 (s, 3H),4.30 (q, 2H, J=Hz), 5.8-6.6 (m, 2H), 6.7-7.1 (m, 5H).

EXAMPLE 16 2-(3,4-dimethoxycinnamyl)-4-methoxyphenol Step A: Preparationof 2-(3,4-dimethoxycinnamyl)-4-methoxy-1-O-methoxymethylphenol

From 1.00 g (6.02 mmol) of 3,4-dimethoxybenzaldehyde there was preparedas in Step E of Example 14, 1.63 g (80%) of2-(3,4-dimethoxycinnamyl)-4-methoxy-1-O-methoxymethylphenol as acolorless glass. NMR (CDCl₃) δ3.43 (s, 3H), 3.46 (trans), 3.68 (cis) (d,2H, J=7 Hz, trans:cis=3:1), 3.78 (s, 3H), 3.88 (s, 6H), 5.10 (trans),5.15 (cis) (s, 2H), 5.75-6.5 (m, 2H), 6.6-7.1 (m, 6H).

Step B: Preparation of 2-(3,4-dimethoxycinnamyl)-4-methoxyphenol

Prepared from 1.00 g (2.90 mmol)2-(3,4-dimethoxycinnamyl)-4-methoxy-1-O-methoxymethylphenol as in Step Fof Example 14 to afford 0.66 g (76%) of2-(3,4-dimethoxycinnamyl)-4-methoxyphenol as a colorless glass. NMR(CDCl₃) δ3.45 (trans), 3.66 (cis) (d, 2H, J=7 Hz, trans:cis=3:1) 3.78(s, 3H), 3.88 (s, 6H), 5.7-6.6 (m, 2H), 6.65-7.0 (m, 6H).

EXAMPLE 17 2-(p-methylthiocinnamyl)-4-methoxyphenol Step A: Preparationof 2-(p-Methylthiocinnamyl)-4-methoxy-1-methoxymethylphenol

From 0.920 g (6.10 mmol) of p-methylthiobenzaldehyde there was preparedas in Step E of Example 14 1.68 g (86%) of2-(p-methylthiocinnamyl)-4-methoxy-1-methoxymethylphenol as a colorlessglass. NMR (CDCl₃) δ2.40 (s, 3H), 3.40 (m, 5H), 3.70, s (3H), 5.0 (cis),5.05 (trans) (s, 2H, trans:cis=4:1) 5.75-6.4 (m, 2H), 6.6-7.2 (m, 5H).

Step B: Preparation of 2-(p-Methylthiocinnamyl)-4-methoxyphenol

From 1.00 g (3.02 mmol) of 2-(p-methylthiocinnamyl)4-methoxy-1-methoxymethylphenol there was prepared as in Step F ofExample 14 0.72 g (83%) of 2-(p-methylthiocinnamyl)-4-methoxyphenol as acolorless glass. NMR (CDCl₃) 2.40 (s, 3H), 3.40 (trans), 3.55 (cis) (d,2H, J=7 Hz, trans:cis=4:1), 3.70 (s, 3H), 5.7-6.4 (m, 2H), 6.6-7.2 (m,5H).

What is claimed is:
 1. A compound of formula (II) ##STR6## or apharmaceutically acceptable salt thereof whereinR is(a) COOR² wherein R²is H or C₁₋₆ alkyl; (b) loweralkoxy; (c) halo C₁₋₆ alkylcarbonyl; (d)halo; (e) lowerhaloalkyl; (f) hydroxyloweralkyl; or (g) cyano; m is 1 or2; A is unsubstituted or substituted heteroaryl selected from a groupconsisting of:(1) thienyl; (2) benzothienyl; (3) furyl; (4) benzofuryl;(5) pyrryl; (6) pyridyl; (7) tetrazolyl; or (8) imidazolyl;theheteroaryl above being substituted with one or two of R¹ wherein R¹ is(1) hydrogen; (2) halo; (3) loweralkoxy; (4) lower alkylthio; (5) loweralkyl sulfinyl; (6) lower alkyl sulfonyl; (7) loweralkyl; (8) loweralkanoyl; (9) haloloweralkyl; (10) --COOH; (11) --COOC₂ H₅ ; (12)hydroxyloweralkyl; (13) halo loweralkanoyl or (14) loweralkanoyloxy. 2.The compound of claim 1 whereinR is loweralkoxy; m is 1; and A isunsubstituted or substituted heteroaryl selected from a group consistingof(1) thienyl; (2) benzothienyl; (3) imidazolyl; or (4) pyrryl.
 3. Thecompound of claim 1 whereinR is methoxy;m is 1; and A is(a) ##STR7## (b)##STR8##
 4. A method of treating or decreasing topical inflammationcomprising the administration to a mammalian species in need of suchtreatment of a therapeutically effective amount of a compound of formula(II) ##STR9## or a pharmaceutically acceptable salt thereof wherein Ris(a) COOR² wherein R² is H or C₁₋₆ alkyl; (b) loweralkoxy; (c) haloC₁₋₆ alkylcarbonyl; (d) halo; (e) lowerhaloalkyl; (f) hydroxyloweralkyl;or (g) cyano; m is 1 or 2; A is unsubstituted or substituted heteroarylselected from a group consisting of:(1) thienyl; (2) benzothienyl; (3)furyl; (4) benzofuryl; (5) pyrryl; (6) pyridyl; (7) tetrazolyl; or (8)imidazolyl;the heteroaryl above being substituted with one or two of R¹wherein R¹ is (1) hydrogen; (2) halo; (3) loweralkoxy; (4) loweralkylthio; (5) lower alkyl sulfinyl; (6) lower alkyl sulfonyl; (7)loweralkyl; (8) lower alkanoyl; (9) haloloweralkyl; (10) --COOH; (11)--COOC₂ H₅ ; (12) hydroxyloweralkyl; (13) halo loweralkanoyl; or (14)loweralkanoyloxy.
 5. The method of treatment of claim 4 whereinR isloweralkoxy; m is 1; and A is unsubstituted or substituted heteroarylselected from a group consisting of(1) thienyl; (2) benzothienyl; (3)imidazolyl; or (4) pyrryl.
 6. The method of treatment of claim 4whereinR is methoxy; m is 1; and A is(a) ##STR10## (b) ##STR11##
 7. Apharmaceutical composition for treating topical inflammation comprisinga pharmaceutical carrier and an effective amount of a compound offormula (II) ##STR12## or a pharmaceutically acceptable salt thereofwherein R is(a) COOR² wherein R² is H or C₁₋₆ alkyl; (b) loweralkoxy;(c) halo C₁₋₆ alkylcarbonyl; (d) halo; (e) lowerhaloalkyl; (f)hydroxyloweralkyl; or (g) cyano; m is 1 or 2; A is unsubstituted orsubstituted heteroaryl selected from a group consisting of:(1) thienyl;(2) benzothienyl; (3) furyl; (4) benzofuryl; (5) pyrryl; (6) pyridyl;(7) tetrazolyl; or (8) imidazolyl;the heteroaryl above being substitutedwith one or two of R¹ wherein R¹ is (1) hydrogen; (2) halo; (3)loweralkoxy; (4) lower alkylthio; (5) lower alkyl sulfinyl; (6) loweralkyl sulfonyl; (7) loweralkyl; (8) lower alkanoyl; (9) haloloweralkyl;(10) --COOH; (11) --COOC₂ H₅ ; (12) hydroxyloweralkyl; (13) haloloweralkanoyl; or (14) loweralkanoyloxy.
 8. The composition of claim 7whereinR is loweralkoxy; m is 1; and A is unsubstituted or substitutedheteroaryl selected from a group consisting of(1) thienyl; (2)benzothienyl; (3) imidazolyl; or (4) pyrryl.
 9. The composition of claim7 whereinR is methoxy; m is 1; and A is(a) ##STR13## (b) ##STR14##